2-[3-cyano-4-(2-methylpropoxy)phenyl]-4-methylthiazole-5-carboxylic acid (also known as “febuxostat” and “TMX-67”) is a potent, non-purine selective inhibitor of xanthine oxidoreductase. Febuxostat 40 and 80 mg once daily (QD) is approved in the United States for the chronic management of hyperuricemia in patients with gout. Gout is a disease that results from the deposition of urate crystals in synovial fluid and other tissues when there is an oversaturation of urate in the blood. Febuxostat is a potent selective inhibitor of the xanthine oxidoreductase enzyme (or xanthine oxidoreductase inhibitor) that is required for the synthesis of uric acid.
The xanthine oxidoreductase enzyme can be present in two different forms (See, Enroth C, et al., “Crystal structures of bovine milk xanthine dehydrogenase A and xanthine oxidase: structure-based mechanism of conversion,” Proc. Natl. Acad. Sci. USA, 97(20):10723-8 (Sep. 26, 2000)). In one form, the xanthine oxidoreductase enzyme is synthesized as xanthine dehydrogenase. This form of the enzyme exhibits a very low reactivity with oxygen. However, under stress or disease conditions, such as ischemia reperfusion injury and congestive heart failure, xanthine dehydrogenase can undergo the formation of intramolecular disulfide bonds or proteolytic cleavage, which converts the enzyme to the second form, xanthine oxidase. Xanthine oxidase exhibits a high reactivity with oxygen. Therefore, the synthesis of uric acid from xanthine and hypoxanthine by the xanthine oxidoreductase enzyme in the form of xanthine oxidase is associated with the generation of oxygen free radicals, such as superoxide anion and hydrogen peroxide. These free radicals are capable of causing a variety of toxic activities in the body such as inactivation of proteins, DNA breakdown, lipid peroxidation (which causes cell membrane disruption) and increasing pro-inflammatory cytokines.
A number of disease conditions are associated with elevated xanthine oxidoreductase activity, especially, elevated xanthine oxidase activity. Such diseases include, but are not limited to, hyperuricemia, hypertension, metabolic syndrome, diabetes, myocardial ischemia, atherosclerosis, stroke, congestive heart failure, inflammatory bowl disease, renal disease progression, prostatitis, sleep apnea and autoimmune diseases. Hyperuricemia is also associated with a number of disease conditions, such as renal injury and hypertension.
Allopurinol is used in the treatment of hyperuricemia. Allopurinol has been shown to prevent the renal injury and hypertension associated with hyperuricemia by inhibiting xanthine oxidoreductase, thus reducing uric acid levels. In contrast, it has been found that the extent of protection against renal injury and hypertension in subjects suffering hyperuricemia is lower in subjects treated with the uricosuric agent benziodarone. Benziodarone does not inhibit xanthine oxidoreductase activity, but instead reduces plasma uric acid levels by increasing the excretion of uric acid in the kidney (See, Mazzali M, et al., “Elevated uric acid increases blood pressure in the rat by a novel crystal-independent mechanism,” Hypertension, 38:1101-1106 (2001) and Mazzali M, et al., “Hyperuricemia induces a primary renal arteriolopathy in rats by a blood pressure-independent mechanism,” Am. J. Physiol Renal Physiol., 282:F991-F997 (2002)). Therefore, there is a need in the art for new dosage forms that not only reduce uric acid levels in subjects suffering hyperuricemia, but are also capable of maintaining a high level of (namely, at least 80%) inhibition of xanthine oxidoreductase activity in a subject in order to protect subjects receiving these dosage forms throughout their treatment regimen (i.e., dosing interval which is typically twenty-four hours) against increasing concentrations of oxygen free radicals.
As referenced above, another treatment for hyperuricemia is with the compound febuxostat. Extensive pharmacokinetic and pharmacodynamic data have established that maintaining a concentration of febuxostat in plasma over a prolonged period of time provides similar efficacy to treatment with high doses of the drug. Generally, these studies have shown that maintaining a febuxostat plasma concentration of 100 ng/ml is required to provide 95% or greater inhibition of xanthine oxidase. Currently, there the only commercially available formulations of febuxostat are immediate release formulations. There are no currently commercially available extended or delayed release formulations of febuxostat. Therefore, a formulation of febuxostat that maintains the drug concentration above the critical concentration of 100 ng/ml for an extended period of time is expected to result in higher efficacy of the drug, and would be a desirable treatment option for the control of hyperuricemia, gout, and many other disease states.